Realism needed about the benefits and risks of taking part in HIV cure studies

A significant proportion of people living with HIV would be willing to take part in a study towards a cure for HIV, research presented at the 21st International AIDS Conference (AIDS 2016) in Durban, South Africa last month shows. However, some potential participants may not fully understand that taking part in an early-phase study is highly unlikely to afford any personal clinical benefit, but might have the potential to cause harm.

There is “an ethical imperative to understand the motivations, decision‐making, expectations and comprehension of potential trial participants,” researchers say. Improved community engagement and education appears to be needed.

According to an Australian survey, 82% of people living with HIV would be ‘willing’ or ‘very willing’ to participate in a clinical trial related to HIV cure research. However, respondents would be less willing to participate if it:

• would increase their susceptibility to illness (87%)
• risked developing resistance to current antiretrovirals (79%)
• resulted in an unpredictable viral load for up to one year (63%)
• involved weekly visits to a medical clinic for several months (40%).

In contrast, 31% would be more willing to participate if it would help future generations but offered no personal benefit.

When asked about the possible characteristics or benefits of a cure, respondents indicated that the most important was not passing the virus to others. Also very important was not being at risk of ill‐health due to advanced HIV disease.

Other outcomes were ranked lower: stopping using HIV medications, being considered a person without HIV infection, not getting HIV again for a second time, fewer medical visits.

United States

More detailed findings came from a survey completed by 400 Americans living with HIV, 77% of whom were male. Whereas 65% were white, 17% were black, 12% Hispanic, 4% mixed and 2% Asian. Alongside the survey, interviews were conducted with 36 people living with HIV, clinicians, researchers, bioethicists and regulators. Results were reported in a series of posters.

Whereas the Australian data came from a general survey of HIV-positive people (HIV Futures 8) that covered a range of issues, the American participants were connected to HIV cure research networks and were recruited to a survey about an HIV cure. They could be expected to be better informed about cure issues and more interested in taking part in a cure study.  

Despite this, 8% thought a cure for HIV was already in existence. A further 27% thought a cure would probably be available within five years and 33% thought it would only take ten years.

Asked about the potential benefits of taking part in cure-related research, benefits to the wider society ranked highly. Helping find a cure for HIV (95%), helping others with HIV in the future (90%) and contributing to scientific knowledge (88%) were among the most cited reasons.

Such social benefits could have an emotional impact – ‘feeling good about contributing to HIV cure research’ was an important personal benefit (80%). Respondents also hoped to gain knowledge about their own health or HIV (78%) and new treatment options (77%). Getting better access to medical care was cited by a number of participants, but relatively few were motivated by financial compensation.

In terms of clinical benefits, many respondents hoped that they might increase their immune system’s ability to fight HIV (92%), reduce the reservoir of HIV in their body (85%), control viral load in the absence of treatment (84%) or reduce the risk of transmitting the virus to a sexual partner (79%). However the researchers comment, “Early phase research does not confer projected direct clinical benefits and there is the possibility of harm while advancing medical knowledge.”

The survey showed participants to be less aware of risks than of benefits. Asked which potential risks would discourage them from participating in an HIV cure-related study, respondents indicated a number of possible harms, but in lower numbers.

In terms of clinical risks, increased cancer risk (49%), developing resistance to antiretrovirals (37%), side-effects (30%) and the known risks of stopping HIV medications (30%) could discourage participation.

Study procedures presenting the greatest barriers were lumbar punctures (26%), bone marrow biopsies (22%), lymph node biopsies (13%) and rectal biopsies (13%). Specific side-effects such as hair loss (32%) and vomiting (23%) would be off-putting. Practical problems like trouble parking at the clinic (20%) or getting transport to it (17%) could also discourage trial participation.

A smaller group of people living with HIV were interviewed and asked what might be ‘too much risk’ for them to take part. Some of their responses were:

“Trying an approach never tested on humans.”

“Gene manipulations that result in cancers probably would be the most frightening and unbearable.”

“If I were to become resistant to the drugs that are saving my life at present.”

“A risk that would have me end up in irreversibly poorer health than I am now.”

“Greater than 1% risk of death.”

Clinicians and researchers who were interviewed also had views on what would constitute ‘too much risk’. Most said that stem cell transplants in otherwise healthy, cancer-free participants who are stable and suppressed on antiretroviral therapy would be too risky. Others mentioned anti-programmed cell death protein 1 that has shown significant toxicities in animal studies.

Likewise, regulators who were interviewed said that some studies were too risky to go ahead. If there was either insufficient information to assess risk or insufficient potential benefits to outweigh the risks, approval would not be given. A poorly designed study would be unlikely to bring us closer to a cure, while exposing participants to risk.

One particular study procedure that could expose participants to harm is an analytical treatment interruption. Antiretroviral treatment would need to be stopped, in order to assess time to viral rebound or predictors of rebound. Of the survey respondents, 26% indicated they were very willing and 42% somewhat willing to interrupt their treatment.

During interviews, motivations for agreeing to stop included a desire to help find a cure (“Knowing that you are a part of something that may help a lot of people in the future”), past experiences with treatment interruptions (“They took me off the medications for three years; and for three years, my CD4 count never dropped below 550.”) and financial benefits (“It would be less expensive not having to take meds for 6 months”).

But other participants saw a treatment interruption as something that would be ‘too much risk’. They were concerned that they might experience a rise in viral load, could transmit HIV, could develop resistance or could have opportunistic infections.

Recommendations

Given some of the misconceptions and concerns which emerged from the study, the American researchers say that a comprehensive education and stakeholder engagement plan is needed. They make a large number of recommendations including:

• People living with HIV should be engaged, at an early stage, in HIV cure research, using Good Participatory Practice (GPP) guidelines. 
• Transparency about the research goals, process and anticipated outcomes is crucial to combatting rumours and setting realistic expectations of early phase research.
• Researchers have an ethical duty to convey risks to potential study participants and to explain the lack of expected clinical benefits.
• HIV cure research participants should know that interventions are experiments that evaluate basic safety and are meant to generate knowledge for the benefit of society.
• Perceptions of what constitutes ‘too much risk’ should be taken into account when designing and approving studies; there should be safeguards in place to protect participants from taking unacceptable risks.
• Risks taken by study participants must be minimised and be reasonable in relation to the scientific importance of the research knowledge that may be generated.
• Treatment fatigue should not be used as a way to attract volunteers to studies that involve an analytical treatment interruption.